Modafinil: Preclinical, clinical, and post-marketing surveillance - A review of abuse liability issues

Department of Psychiatry and Behavioral Sciences, Medical University of South Carolina, Charleston, South Carolina 29425, USA.
Annals of Clinical Psychiatry (Impact Factor: 2.53). 04/2004; 16(2):101-9. DOI: 10.1080/10401230490453743
Source: PubMed

ABSTRACT Modafinil is an agent that is frequently used in the treatment of narcolepsy. More recently it has been used in the treatment of a variety of psychiatric, neurological, and medical illnesses. Due to its ability to improve wakefulness, modafinil has been viewed as a stimulant. Based on the potential for modafinil to become widely used in a variety of syndromes and settings, evidence from preclinical in vitro and in vivo studies, human laboratory studies, and post-marketing experiences examining the potential abuse liability of modafinil were reviewed. Initial evidence suggests that modafinil has limited potential for large-scale abuse.

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    • "Together, these recent findings indicate that modafinil, even when taken alone, may have addictive potential. Despite its profile as a modest reinforcer there are no published case reports of addiction to modafinil, and several studies have reported that modafinil lacks a drug-induced " high " [25] [26] [27] [28]; for review see [28]. This may be because modafinil is used orally, and has a relatively slow peak time (2–4 h) and long half-life (10–12 h), compared to the stimulants of abuse (i.e., smoked or snorted cocaine and methamphetamine). "
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    ABSTRACT: Modafinil is a wake-promoting drug effective at enhancing alertness and attention with a variety of approved and off-label applications. The mechanism of modafinil is not well understood but initial studies indicated a limited abuse potential. A number of recent publications, however, have shown that modafinil can be rewarding under certain conditions. The present study assessed the reinforcing properties of modafinil using conditioned place preference and locomotor sensitization in mice. Experiment 1 examined a high dose of modafinil (75mg/kg) as well as its interactions with cocaine (15mg/kg). Cocaine alone and modafinil co-administered with cocaine induced sensitization of locomotor activity; modafinil alone showed little or no locomotor sensitization. Animals given modafinil alone, cocaine alone, and modafinil plus cocaine exhibited a strong and roughly equivalent place preference. When tested for sensitization using a low challenge dose of modafinil, cross-sensitization was observed in all cocaine-pretreated mice. Experiment 2 examined a low dose of modafinil that is similar to the dose administered to humans and has been shown to produce cognitive enhancements in mice. Low dose modafinil (0.75mg/kg) did not produce conditioned place preference or locomotor sensitization. Together, these results suggest that modafinil has the potential to produce reward, particularly in cocaine addicts, and should be used with caution. However, the typical low dose administered likely moderates these effects and may account for lack of addiction seen in humans.
    Behavioural brain research 08/2012; 235(2):105-12. DOI:10.1016/j.bbr.2012.07.039 · 3.39 Impact Factor
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    • "In animal testing it has been found to attenuate reinstatement of meth self-administration (Reichel and See, 2010). Also, modafinil appears to have lower abuse potential than methylphenidate or amphetamine (Myrick et al., 2004). Modafinil improves cognition and mood (Turner et al., 2004; Taneja et al., 2007), and has shown efficacy in the treatment of child and adult ADHD (Lindsay et al., 2006). "
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    ABSTRACT: Modafinil was tested for efficacy in decreasing use in methamphetamine-dependent participants, compared to placebo. This was a randomized, double-blind, placebo-controlled study, with 12 weeks of treatment and a 4-week follow-up. Eight outpatient substance abuse treatment clinics participated in the study. There were 210 treatment-seekers randomized, who all had a DSM-IV diagnosis of methamphetamine dependence; 68 participants to placebo, 72 to modafinil 200mg, and 70 to modafinil 400mg, taken once daily on awakening. Participants came to the clinic three times per week for assessments, urine drug screens, and group psychotherapy. The primary outcome measure was a methamphetamine non-use week, which required all the week's qualitative urine drug screens to be negative for methamphetamine. Regression analysis showed no significant difference between either modafinil group (200 or 400mg) or placebo in change in weekly percentage having a methamphetamine non-use week over the 12-week treatment period (p=0.53). Similarly, a number of secondary outcomes did not show significant effects of modafinil. However, an ad-hoc analysis of medication compliance, by urinalysis for modafinil and its metabolite, did find a significant difference in maximum duration of abstinence (23 days vs. 10 days, p=0.003), between those having the top quartile of compliance (>85% of urines were positive for modafinil, N=36), and the lower three quartiles of modafinil 200 and 400mg groups (N=106). Although these data suggest that modafinil, plus group behavioral therapy, was not effective for decreasing methamphetamine use, the study is probably inconclusive because of inadequate compliance with taking medication.
    Drug and alcohol dependence 08/2011; 120(1-3):135-41. DOI:10.1016/j.drugalcdep.2011.07.007 · 3.28 Impact Factor
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    • "Modafinil and morphine CPP reinstatement P Tahsili-Fahadan et al shown). This revealed that modafinil alone did not have a reward valence in this paradigm, consistent with previous reports indicating its low abuse potential (Deroche- Gamonet et al, 2002; Myrick et al, 2004). In Experiment 2, animals conditioned with morphine (8 mg/kg) showed a significant preference for the morphinepaired side on the post-conditioning day (preference score ¼ 281 ± 34 s; t-test, t(43) ¼ À9.786, po0.001; data not shown). "
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    ABSTRACT: Opiate addiction is characterized by high rates of relapse even after long periods of abstinence, requiring new relapse-prevention treatments that do not have abuse potential. Recently, clinical studies suggested that the wake-promoting drug modafinil might decrease relapse in cocaine addicts. In addition, group II metabotropic glutamate receptors (mGlu2/3R) have been suggested as a new therapeutic target for drug addiction. Here, we investigated the ability of modafinil to prevent the acute morphine to promote reinstatement of extinguished preference for morphine, and the involvement of mGlu2/3Rs in this effect. Conditioned place preference (CPP) for morphine was induced in Sprague-Dawley rats, followed by extinction training. Preference for the morphine-paired side was reinstated following extinction by a morphine-priming injection. The results of our study showed that modafinil (300 mg/kg, i.p., but not 100 mg/kg) 30 min before the morphine-priming injection blocked reinstatement of extinguished CPP. The anti-reinstatement effect of modafinil was completely prevented by pretreatment with the selective mGlu2/3 antagonist LY341495. Additional experiments indicated that modafinil alone did not produce a preference, and that modafinil did not alter the expression of morphine CPP or the cueing properties of morphine either 1 or 14 days after morphine CPP conditioning. These data reveal a novel mechanism for modafinil actions, a role for mGlu2/3 receptors in reinstatement of opiate-seeking, and a new therapeutic option to treat relapse in opiate addiction.
    Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology 10/2010; 35(11):2203-10. DOI:10.1038/npp.2010.94 · 7.83 Impact Factor
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